Learning From Flies with Diabetes

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: Diabetes and fruit flies; Dr. Carl Thummel, Professor of Human Genetics, is investigating what these insects can tell us about the disease, and some of his findings may surprise you.
Now is this something that happens to flies in nature, or something that you induce in the lab?

Dr. Thummel: It can happen under any circumstances, just like it could with you and me, because all living animals fundamentally need to handle their energy. So we eat three meals a day and we do that because we need the energy to survive. And we take those nutrients; we burn some of them to do what we need to do day to day, just to maintain our normal existence. And we store a whole bunch of it away so that it's available to us when food is not plentiful. And all animals have to do this, so that when we are fasting, or starving under the worst conditions as an animal, we can survive. It's just a fundamental survival mechanism, and there are regulatory systems that control that energy storage and release, and they are the same in a fly or a person.

Interviewer: And what does a fly with diabetes look like?

Dr. Thummel: Diabetes would not necessarily lead to being overweight. A lot of people actually ask whether you can tell your flies are obese, and sadly you can't. But I just wonder if it's because we're not flies.

Interviewer: Yes.

Dr. Thummel: You know, when you look at them, another fly may look at it and say, you look overweight. What's wrong? But when we look at the flies we don't really see them visually as overweight, and it might be because they have an exoskeleton.

Interviewer: Right.

Dr. Thummel: Unlike us, we have a skeleton inside our body; they have a skeleton outside their body that restricts their size to some degree.

Interviewer: Right.

Dr. Thummel: But if you open them up and you look at their adipose deposits you can see that they are indeed loaded with fat. And we can measure that with assays that we use to measure something called triglycerides, which are stored fat. And that's how we quantify it basically.

Announcer: What's the advantage of investigating diabetes in fruit flies?

Dr. Thummel: That's the real question, right? Why would we want to study these disorders that you and I have in this weird little bug system? And that's where the real strength comes in, because fruit flies have so many advantages for genetic and functional studies. They just aren't present in other more complex animal models like mice, or even zebra fish.
This goes back to about 100 years now of fly genetics that's behind this, and thousands and thousands of genetic stocks that are available to us so that we can manipulate the fly's genome basically in any way we want very quickly, and analyze pathways in great detail... far greater than we could do in another model system.

Interviewer: And can you tempt us with any of your findings?

Dr. Thummel: We're excited about our studies with diabetes now, because we have one of the first genetic models of diabetes. We have genetic diabetic models where through mutation these animals are no longer able to release insulin properly in response to glucose, which is what normally happens. You eat a meal, your glucose levels rise, your pancreatic cells sense that and release insulin, and that causes your peripheral tissues to suck up glucose, to store it away or burn it. And the diabetics are unable to do that for various reasons, either an inability to release insulin properly, or an inability to clear glucose properly. And our different genetic models have defects in both of those pathways. They can't sense glucose or release insulin, or they can't clear it properly, in peripheral tissue.
So we can model more than we had actually expected we would be able to do, really model the major forms of diabetes that are out there. And so we're really working hard on trying to figure out the mechanisms that are involved. Many of the genes we identify are conserved throughout evolution, and so we think it'll have direct relevance for human disease.

Interviewer: One thing I notice that you are studying is the transgenerational effect of diabetes, which is a concept that's really fascinating to me. Can you explain what that is and what you're doing?

Dr. Thummel: This goes back to studies in rodent systems over the last decades, but more profoundly to a human study called the Dutch Hunger Winner, which was at the end of the Second World War when the Nazis had a siege on in Holland. And the Dutch were getting much less food than they normally would get. And those children who were born during this period of low nutrient availability later grew up during a postwar period of prosperity under ideal dietary circumstances. And it turned out that when you looked at these as adults the kids whose mom's were not getting enough nutrition had a higher propensity to diabetes and obesity than their siblings did, who where under ideal dietary circumstances.
This was very interesting, because many studies have shown the same thing in rats and mice. And people hadn't really known what to make out of it.

Interviewer: Right, because it's not like traditional genetics. The parents weren't born with a predisposition to diabetes; they acquired it later. But then they still passed it on to their kids.

Dr. Thummel: You're exactly right. So it means that our own metabolic health isn't just dependent on what we eat and our particular genetics, like we assume. Those are the things we assume are the most important, and they indeed are. But another important factor in our metabolic health is our parents' metabolic health and even our grandparents' or great grandparents.
This has been now receiving a lot of attention. People want to understand the molecular mechanisms behind this non-canonical genetic inheritance, called epigenetic inheritance. And we are tackling it in the fruit fly.

Interviewer: What's an example of how you're approaching that problem in flies?

Dr. Thummel: We have set up stocks of flies that are genetically absolutely identical, so there's no genetic variation in those. And we are taking the parental generation and subjecting them either genetically or through diet to nutrient deprivation; or we're making them conversely obese; too much nutrients. And then we raise their offspring on a normal diet, and we check their metabolic parameters. And we take their offspring and raise them on a normal diet and check their metabolic parameters, and so on.
So we are looking to reproduce the effects in rodents and humans. We have been successful at that, and so now what we're trying to do is get those results reproducible and robust enough so we can start doing molecular studies to get a mechanism.

Interviewer: You've been working with fruit flies for quite a while, and I believe this is sort of a new focus for your lab, a relatively new focus. Why did you decide to make that shift?

Dr. Thummel: As you know, and as everyone knows, over the last ten years we've become very much aware of this increase in both diabetes and obesity in human populations. It's really threatening our health in ways that we never would have envisioned. When I was a kid we could eat Twinkies and drink Coca-cola and we didn't even think about the health consequences of that. It was wonderful.

Interviewer: Yeah.

Dr. Thummel: And now we look at our kids and we actually worry about whether they're drinking too much soda, or are they eating too many junk foods, and indeed, they are. As a population we have more calories available than we need for our day-to-day survival, so we are all living in an epidemic of diabetes and obesity. You can see it around you all the time.
And so this peaked our interest, and really caused us to redirect our research to see how far we could push flies to study those kinds of evolutionarily conserved pathways. And it's been very gratifying to see how well we can model it. Actually it's really surprising, I'll have to say. I am very surprised to see how similar they are.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.